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Hannah Allegretto UPMC Ambulatory Care General Internal Medicine Systemic Lupus Erythematosus Learning Objectives: Discuss the susceptibility and pathophysiology of systemic lupus erythematosus (SLE) Identify the signs and symptoms of SLE Review the diagnostic criteria for SLE List appropriate treatment regimens and monitoring parameters for the management of SLE The Patient: DC is a 59 year old white female presenting to her PCP on March 11, 2013 for a follow up appointment. DC has a history of hyperthyroidism, SLE complicated with nephritis and lupus anticoagulant, seizure disorder, GERD, anxiety/depression, and coronary artery disease s/p CABG. DC presents to the clinic for a f/u appointment and has no current complaints to report. In 2004, DC was diagnosed with lupus nephritis for which she received six cycles of cyclophosphamide and high dose glucocorticoids. Chief Complaint: None Past Medical History: hyperthyroidism, SLE with nephritis and lupus anticoagulant, seizure disorder, GERD, anxiety/depression, and coronary artery disease s/p CABG Allergies: iodine and sulfa (rash) Family History: Sister has hyperthyroidism and SLE Social History: Smoking: 0.25 packs/day for 30 years (7.5 pk-years) – quit March 2008 Alcohol use: stopped drinking after December 2012 hospitalization (seizures) Widowed Current Medications: Aspirin 81mg PO QD Levetiracetam 375mg PO every AM and 750mg PO every PM OS-CAL 500 + D (500mg/200unit) 1 PO TID Lisinopril 40mg PO QD Folic Acid 1mg PO QD Lorazepam 0.5mg PO BID Omeprazole 20mg PO QD Methimazole 30mg PO QD Docusate 100mg PO QD Prednisone 3mg PO QD Atorvastatin 20mg PO QD Tramadol 50mg PO every 8 hours Fluoxetine 40mg PO QD Warfarin 5mg PO daily as directed Review of Systems: Positive: fatigue Negative: rashes, pain Physical Exam: Vitals: BP: 104/68 mmHg P: 72 Wt: 43kg (94lbs) General: thin appearing female in no acute distress CV: RRR, S1 and S2 normal Thyroid: firm but not enlarged Skin: warm and dry Laboratory Findings: (3/27/2013) INR: 2.5 BMI: 16.79kg/m2 SCr: 1.4mg/dL BUN:22 mg/dL T4: 6.5mcg/dL Lipids: o Cholesterol 156mg/dL o HDL: 59mg/dL o LDL: 76mg/dL o Trig: 107mg/dL T Score: -3.1 ESR: 19 Discussion of Systemic Lupus Erythmatosus (SLE): Background: Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting autoimmune disease characterized by inflammation, vasculitis, and vasulopathy.1 In autoimmune diseases, the immune system begins to attack the parts of the body that it would normally protect, leading to inflammation and tissue damage. SLE can manifest in patients ranging from mild arthritis symptoms to more serious conditions such as nephritis and pericarditis. Currently, it is estimated that at least 1.5 million Americans, and at least five million people throughout the world, suffer from lupus. Lupus is more prevalent in women than men (10:1), and often affects them during their childbearing years. The majority of SLE cases are diagnosed between the years of 15 and 45. SLE accounts for 70% of all lupus cases, with half of these individuals experiencing involvement of a major organ. Organ damage progresses over time and is usually more severe in African American patients.2,3 Early identification and control of SLE is imperative to maintain a high quality of life for individuals affected. SLE Susceptibility and Pathophysiology: Although the exact cause of lupus is unknown, several areas of the disease are being investigated in order to gain a better understanding of the causes of SLE, such as genetics, biomarkers, and disease progression.4 SLE patients develop abnormalities within the immune system leading to the production of autoantibodies. SLE has been associated with over 100 autoantibodies, which differ from patient to patient. Major histocompatibility complex genes have been extensively studied in relation to SLE contribution and HLA class II gene polymorphisms are associated with the presence of autoantibodies present in SLE. The most common autoantibodies found in SLE patients are antinuclear antibodies (ANA), including antiphospholipid antibody (APLA), anti-SM antibody, and anti-dsDNA antibody. SLE tends to occur in families, but gene abnormalities are not completely understood. It is thought that an individual needs at least four susceptibility genes in order to develop SLE.1 Many genes implicated in the development of SLE are involved with Blymphocyte activation, apoptosis, and the interferon signaling pathway. Along with genetic factors contributing to the disease, environmental and hormonal factors have also been linked with the expression of SLE. Sunlight has been found to exacerbate the disease due to the promotion of apoptosis. In SLE, apoptosis is slowed, leading to an inflammatory response in the skin which causes a lupus rash. Epstein-Barr virus (EBV) has also been investigated as a possible factor contributing to the development of lupus. EBV can interact with B cells, and a large number of B cells infected with this virus have been found in lupus patients.7 Because SLE has been largely associated in women during childbearing years, hormonal factors have been implicated in the disease. Hormone replacement therapy (HRT) was shown to increase mild to moderate flares compared to patients receiving placebo. Oestrogen-containing oral contraceptives have been discouraged in women with SLE due to reports of serious disease flares, but more recent studies suggest that patients with mild, stable forms of the disease who are antiphospholipid antibody negative, may be able to use this form of contraception successfully. A high thrombotic risk still remains in lupus patients, even if antiphospholipid antibodies are absent.7 Signs and Symptoms: Due to a wide range of organs affected by lupus, symptoms can vary from patient to patient, but most commonly include: Extreme fatigue Joint pain/swelling Anemia Headaches Fever Abnormal blood clotting Butterfly rash across cheeks/nose Mouth or nose ulcers Raynaud’s Phenomenon Photosensitivity SLE Diagnosis: SLE can present with symptoms similar to other diseases, which can delay the proper diagnosis of this disease. Physical and laboratory evidence found in SLE patients includes joint swelling, proteinuria and cell casts, fluid around lungs/heart, and a positive ANA test.6 Along with laboratory findings aiding in the diagnosis of SLE, the following criteria have been developed to simplify the diagnosis of SLE. Four out of the following eleven criteria are required for a diagnosis of SLE: Malar rash Nonerosive arthritis Hematologic disorder Discoid rash Plueritis or pericarditis Immunologic disorder Photosensitivity Renal disorder Positive ANA test Oral ulcers Neurologic disorder SLE Treatment: SLE patients should be referred to a rheumatologist for several reasons including confirmation of the diagnosis, assessment of activity and severity, management of uncontrolled disease, and in other special circumstances (pregnancy, antiphospholipid syndrome). Lifelong monitoring of disease will be required for most SLE patients. Patient education is a very important aspect of SLE therapy, as the disease is very complex and unpredictable. Along with patient education, pharmacologic therapy is needed in virtually all SLE patients. Mild SLE: Topical suncreens Topical glucocorticoid preparations NSAIDS o Can put patient on H2 blocker or PPI to counteract GI damage from NSAID Hydroxychloroquine 200-400MG/DAY: o Patients should get ophthalmologic exam at 6-12 months because known retinal damage with doses >400mg/day Oral glucocorticoids: o <10mg prednisone daily Serious, life-threatening, or organ-threatening SLE: organ involvement may lead to irreversible damage, require care by a specialist High dose glucocorticoids: o Methylprednisolone 500-1000mg IV x 3-5 days then 1-1.5mg/kg/day then taper ASAP o Patients can often become controlled on 10-20mg prednisone daily Immunosuppresive/cytotoxic agents: o Cyclophosphamide9: lowers autoantibody levels, used in conjunction with glucocorticoids 500-1000mg/m2 IV monthly for 6 months, then every 3 months for 1-2 years For nonresponders, may try 50mg/kg daily for 4 days (high dose therapy) o Azathrioprine3: used as an alternative for cyclophosphamide 1-3 mg/kg/day o Mycophenolate : lower relapse rate than cyclophosphamide Inhibits B and T cell proliferation and antibody formation 1-3g/day along with steroids o Methotrexate: considered “steroid-sparing” because many patients require lower doses of steroids while on this medication Up to 20mg weekly in a single dose o Benlysta (Belimumab): monoclonal antibody – B-lymphocyte stimulator specific inhibitor – helps decrease disease activity, flares, and steroid use 1-10mg/kg IV infusion over 1 hour on days 0, 14, and 28, then every 28 days until 48 weeks. 10mg/kg IV was found significant10 Monitoring: Lifelong monitoring required for the early detection of flares and initiation of appropriate therapy. The following should be obtained at all follow up visits: o CBC w/ diff o Platelet count o Creatinine measurement o Urinalysis w/ 24-hour urine collection for protein o Cholesterol o Calcium Changes in the results of certain laboratory tests such as ESR, complement levels (decrease), increase in antidsDNA level, and a decrease in hemoglobin can be an early prediction of a flare Frequency of follow up visits determined by activity and severity of disease Assessment and Plan for DC: 1. SLE with nephritis o Continue prednisone 3mg PO daily o Goals: reduce frequency and severity of flares, prevent worsening of renal function o Monitoring: signs/symptoms of disease, CBC and urinalysis at each follow up visit 2. Antiphospholipid antibody syndrome o Continue warfarin 5mg PO daily o Continue aspirin 81mg PO daily o Goals: INR: 2-3 o Monitoring: INR every 4 weeks, abnormal bleeding/bruising continuously 3. Hyperthyroidism o Continue methimazole 30mg PO daily o Goals: T4: 4.5-12.5 o Monitoring: signs of anxiety, appetite increase, increased sensitivity to light, rapid heartbeat, and sudden weight loss continuously 4. Seizure disorder o Continue levetiracetam 375mg PO every AM and 750mg PO every PM o Goals: prevention of seizures, serum concentration of 5-45mcg/mL o Monitoring: unusual changes in behavior continuously, seizure activity continuously, serum concentration every 6 months and with any dosage changes 5. Hypertension o Continue lisinopril 40mg PO daily o Goal: BP <140/90mmHg o Monitoring: serum potassium every 6 months, patient to report any headaches and blurry vision continuously 6. Hyperlipidemia o Continue atorvastatin 20mg PO daily o Goals: LDL <100mg/dL HDL >60mg/dL Trig <150mg/dL o Monitoring: lipid panel and LFT’s every 6 months, continuous reporting of any symptoms of muscle weakness 7. Osteoporosis: o Initiate alendronate 70mg PO once weekly8 o o Continue OS-CAL 500 + D (500mg/200unit) 1 PO TID Goal: prevention of bone fractures, preservation of height (<1cm of loss), no change of an increase in bone mineral density Monitoring: central bone mineral density scan in 1 year o 8. GERD: o Continue omeprazole 20mg PO daily o Goal: prevention of heartburn and erosion o Monitoring: continuously for signs of indigestion/heartburn 9. Anxiety/Depression/Possible Pain Management o Continue fluoxetine 40mg PO daily o Continue lorazepam 0.5mg PO twice daily o Continue tramadol 50mg PO Q8H o Goal: Prevent anxiety attacks, any pain, and feelings of depression o Monitoring: number of depressed days and anxiety attacks per month, unusual changes in behavior, monitor pain scale continuously 10. General Health o Continue docusate 100mg PO daily o Continue folic acid 1mg PO daily References: 1. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol. 2003; 56:481-90. 2. Lupus Foundation of America. Statistics on Lupus. Cases of Lupus. http://www.lupus.org/webmodules/webarticlesnet/templates/new_newsroomreporters.aspx?articleid=247&zoneid =60 (accessed 2013 Apr 12). 3. Gladman DD, Urowitz MB, Esdaile JM et al. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum. 1999; 42:1785-96. 4. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Lupus. Handout on Health: Systemic Lupus Erythematosus. http://www.niams.nih.gov/Health_Info/Lupus/#Lupus_9 (accessed 2013 April 13). 5. Sherer Y, Gorsein A, Fritzler MJ et al. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum. 2004; 34: 501-37. 6. Lupus Research Institute. About Lupus. Lupus Diagnosis. http://www.lupusresearchinstitute.org/lupusfacts/lupus-diagnosis (accessed 2013 April 14). 7. D’Cruz DP, Khamashta MA, Hughes GRV et al. Systemic lupus erythematous. Lancet. 2007; 369:587-96. 8. Cosman F, Lindsay R, LeBoff MS et al. National Osteoporosis Foundation: Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2013; 1-54. 9. Petri M, Brodsky RA, Jones RJ et al. High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial. Arthritis Rheum. 2010; 62: 1487-93. 10. Navarra SV, Guzman RM, Gallacher AE et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011; 377:721-31.